Project summary Spinal cord injury (SCI) interrupts motor control pathways between supraspinal and spinal sensorimotor networks. This disruption results in impairment of gait and sensation, chronic decreased quality of life (QOL), and numerous medical complications. In human studies of chronic SCI, lumbar electrical epidural stimulation (EES) based rehabilitation has allowed weight-bearing and unprecedented voluntary stepping in motor complete patients. These results establish that even severe complete SCIs have intact axons spared through the injury site. EES activates dorsal sensory roots to raise excitability of residual intact locomotor circuitry in the spinal cord. This allows otherwise silent descending inputs to become effective, permitting voluntary motion. Although impressive, ES based rehabilitation has not been adequate to restore balanced independent gait in the community setting. If applied during subacute rehabilitation, a period of increased neuroplasticity, this strategy may engender a greater level of permanent recovery. To address inadequate supraspinal drive we will use deep brain stimulation (DBS) of the mesencephalic locomotor region (MLR) to ?overdrive? the stepping initiation center. We have previously developed protocols for MLR DBS and EES in a porcine contusion SCI model but have not combined them. In this project with 2:1 treatment:controls, we propose testing DBS and ES, together with developing a closed-loop perturbation and response protocol, to provide feedback driven stability and balance during weight supported stepping. In Aim 1, Yucatan minipigs with severe T9 SCI will be implanted with both MLR DBS and lumbar ES electrodes and undergo intensive rehabilitation for 3 months. In Aim 2 we test to what extent postural correction can be achieved by asymmetric modification of stimulus parameters in response to a posterior pelvic mounted inertial measurement unit coupled to a PID controller. Primary outcome measures include extent recovery of locomotion, time-walked testing, capacity to achieve unassisted weight support and structural plasticity of the reticulospinal tract. Measures will be acquired using state of the art kinematic analysis and telemetry-electromyography. In histological analysis after neuroanatomical tracing we determine if MLR- DBS causes axonal structural plasticity. Our aims align with the NIBIB mission statement by testing a multidisciplinary bioengineering approach in a clinically relevant and translational paraplegia model. ES and DBS technology has been applied in other clinical conditions including neuropathic pain and Parkinson?s disease. Thus, if successful, the translational path would be accelerated. The combined neuromodulation and rehabilitative intervention is relevant to public health, as it may fundamentally improve recovery from SCI and render subacute neurorehabilitation more effective allowing allow community-setting ambulation, supplanting wheelchair use and increasing QOL for individuals with SCI.